Safety questions remain for insulin peglispro.

Action Points

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The novel basal insulin peglispro works at least as well as insulin glargine and may hold an advantage for weight, although questions remain about hypoglycemia and liver harm.

Note that in the IMAGINE 2 study, alanine aminotransferase was at least three times the upper limit of normal in 2.3% with peglispro compared with 0.6% with insulin glargine, although no patients had a total bilirubin at least twice the upper limit of normal.

BOSTON -- The novel basal insulin peglispro works at least as well as insulin glargine (Lantus) and may hold an advantage for weight, although questions remain about hypoglycemia and liver harm.

In type 2 diabetes, the double-blind IMAGINE 2 trial met noninferiority criteria for the primary endpoint with an HbA1c of 6.9% on the novel agent versus 7.2% with the conventional basal insulin at week 52 (difference -0.29%, 95% CI -0.4 to 0.19).

In type 1 diabetes, the open-label IMAGINE 1 trial showed not only noninferiority to insulin glargine but superiority as well (HbA1c change from baseline -0.69% versus -0.33% at 26 weeks, P<0.001), Satish Garg, MD, of the University of Colorado Denver, and colleagues found.

"To my knowledge, this is the first registration trial of an insulin analogue, whether you talk about basal insulin analogues or rapid acting insulin analogues, that clearly shows that, at the primary endpoint or if you even extend it to a year and a half, there was clearly this significant improvement in the A1c," Garg told attendees.

And in this type 1 diabetes population, insulin peglispro actually was associated with consistent weight loss over the 78 week follow-up compared with weight gain in the glargine group, for an overall mean difference of -1.9 kg, or -4.2 lbs (95% CI -2.5 to -1.2).

Weight gain is usually the concern with insulin, commented Jerome Tolbert, MD, PhD, of Mount Sinai Beth Israel in New York City.

"We don't generally expect patients to lose weight when they're taking insulin but if they're not gaining weight then that's a plus," he told MedPage Today. "I would like to know what is it about this particular insulin that is different than the insulins we have that would do that."

While the trials couldn't explain the difference, Davis suggested one possibility.

"We've always hoped that reducing nocturnal hypoglycemia would potentially have an impact on weight," she said. "That's not always been the case. We know that BIL [peglispro] has a reduced effect on the periphery, and that may result in increased lipolysis and reduced fat storage. That may well we be partly responsible for the difference we see in weight."

"We've all been waiting for a hepato-selective insulin," Stephanie Amiel, MD, of King's College London, acknowledged in the question-and-answer portion of the session.

However, the nocturnal hypoglycemia benefits came at the expense of increased severe hypoglycemia in type 1 diabetes, she noted.

Amiel called the findings "a little disappointing."

"I don't think you can describe better control as an HbA1c that's lower, which is good, but an increased risk of severe hypoglycemia," she said. "Because to have better control, you need both."

J. Hans DeVries, MD, PhD, of the University of Amsterdam called the drug's liver selectivity a "two-edged sword."

Hepatotoxicity Questions

However, both trials showed the liver issues over which peglispro stumbled on the way to the FDA. Drug developer Eli Lilly announced earlier this year that it would delay filing for approval until at least 2017 to "generate additional clinical data."

A spokesperson for the company confirmed that this would mean additional data from another clinical trial.

Peglispro is insulin lispro (Humalog) bound to polyethylene glycol to boost its size beyond that of albumin, which slows its clearance for a half life of about 2 to 3 days and makes it hepato-preferential, Davis said.

In IMAGINE 2, alanine aminotransferase (ALT) was at least three times the upper limit of normal in 2.3% with peglispro compared with 0.6% with insulin glargine (P<0.05). In IMAGINE 1, the rates were 4.5% versus 0.7%, respectively (P=0.041).

No patients in either trial met that threshold along with total bilirubin at least twice the upper limit of normal not attributable to any other cause, criteria known as Hy's law that signal drug-induced liver injury.

Substudies in both trials using MRI to look at liver fat content showed no increase with peglispro but a decrease on insulin glargine in IMAGINE 2 and an increase with peglispro versus decrease with glargine in IMAGINE 1, both statistically significant between group differences.

"But I remind you this is an insulin more specific to the liver," Garg argued. "And up to 78 weeks, we have seen the liver fat is barely going above the normal range. The normal range of liver fat is 5.5 and this at the most went up to 5.8 or 6. The amount of liver fat that causes hepatic steatosis or that causes insulin resistance needs to be hundreds or thousands."

The company will have to convince not only the FDA but also clinicians like Tolbert.

"It would not be a slam dunk [in terms of clinical use] until I felt reassured there was no hepatic toxicity or issues," he said. "That has to be explained. Other than that it seems like it is an improvement over the insulin we have."

Hypoglycemia Questions

Overall, insulin peglispro appeared to have an advantage in reducing the potentially dangerous adverse event of nocturnal hypoglycemia, but at the price of more total and severe hypoglycemia in type 1 disease.

On the positive side, the IMAGINE program "proved it is possible to do a double-blind trial, which nobody does anymore," Fred Storms, MD, PhD, of St. Antonius Hospital in Utrecht, the Netherlands, noted at the session.

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